Lactoferrin is a natural inhibitor of plasminogen activation

Abstract

The plasminogen system is essential for dissolution of fibrin clots, and in addition, it is involved in a wide variety of other physiological processes, including proteolytic activation of growth factors, cell migration, and removal of protein aggregates. On the other hand, uncontrolled plasminogen activation contributes to many pathological processes ( tumor cells' invasion in cancer progression). Moreover, some virulent bacterial species ( or ) bind human plasminogen and hijack the host's plasminogen system to penetrate tissue barriers. Thus, the conversion of plasminogen to the active serine protease plasmin must be tightly regulated. Here, we show that human lactoferrin, an iron-binding milk glycoprotein, blocks plasminogen activation on the cell surface by direct binding to human plasminogen. We mapped the mutual binding sites to the N-terminal region of lactoferrin, encompassed also in the bioactive peptide lactoferricin, and kringle 5 of plasminogen. Finally, lactoferrin blocked tumor cell invasion and also plasminogen activation driven by Our results explain many diverse biological properties of lactoferrin and also suggest that lactoferrin may be useful as a potential tool for therapeutic interventions to prevent both invasive malignant cells and virulent bacteria from penetrating host tissues.

Lactoferrin as potential supplementary nutraceutical agent in COVID-19 patients:in vitroandin vivopreliminary evidences

“…Lf can exert negative regulatory effects on cell migration via inhibition of plasminogen activation and through the regulation of fibrinolysis (Zwirzitz et al, 2018). In addition, we observed an increased platelet count after Lf treatment.…”

“…Recently, it was shown that Lf can regulate the activation of plasminogen and control coagulation cascade with a remarkable antithrombotic activity (Zwirzitz et al, 2018). Especially this Lf property should be stressed considering that COVID-19 is a prothrombotic disease and that the severity of the coagulation parameters impairment is related to a poor prognosis.…”

“…As matter of fact, iron homeostasis involves several iron proteins such as transferrin, ferroportin, hepcidin and ferritin the disorders of which, induced by inflammation, lead to intracellular iron overload and viral replication (Campione et al, 2020). Moreover, Lf seems to regulate the activation of plasminogen and control coagulation cascade with a remarkable antithrombotic activity (Zwirzitz et al, 2018), a very frequent complication of SARS-CoV2 (Marietta et al, 2020). In addition to all these abilities, Lf, as above reported, inhibits the early phase of SARS-CoV (Lang et al, 2011) and post-infection phase of SARS-CoV-2 (Lang et al, 2011;Mirabelli et al, 2020) probably through the binding to HSPGs or to viral particles.…”

Lactoferrin as Protective Natural Barrier of Respiratory and Intestinal Mucosa against Coronavirus Infection and Inflammation

“…A recently investigated effect of Lf is to regulate the activation of the plasminogen, which still adds a value of this molecule in the control of coagulation cascade promoted by the virus. LF can exert negative regulatory effects on cell migration via inhibition of Plg activation and through the regulation of fibrinolysis [85]. This activity was also confirmed by evidence of a peptide with the amino acids sequence derived from lactoferrin shown antithrombotic activity [86].…”

The mannose 6-phosphate/insulin-like growth factor 2 receptor mediates plasminogen-induced efferocytosis

“…These results indicate that Plg‐mediated efferocytosis occurs also in the basic human Plg‐free setup of the assay. This might be either Plg independent, or due to the bovine Plg present in serum that could have pre‐coated apoptotic bodies, since the bovine Plg molecule can also bind to human M6P/IGF2R . Further, the genetic knockout of M6P/IGF2R in phagocytes did not eliminate their efferocytic capacity completely suggesting that other receptor(s) were implicated in recognizing exposed phosphatidylserine and/or other “eat‐me” signals on apoptotic cells, or alternatively, other Plg receptors expressed on macrophages might be involved.…”